X-ray computed tomography (CT) is one of the most commonly used clinical diagnostic imaging technologies. CT is effective to visualize hard tissues due to the inherent density differences between hard and soft tissues. With the assistance of proper contrast agents, CT can also provide high resolution three-dimensional images of soft tissues. Current clinical CT contrast agents are mainly biocompatible small molecular compounds containing heavy elements, such as iodine (Hallouard et al., Biomaterials 2010, 31:6249-68) and barium (Anderson et al., Eur Radiol 2010; 20:2126-34). Small molecular iodinated organic compounds are the most commonly used as intravenous contrast agents for cardiovascular CT imaging, including angiography and myocardial perfusion, image-guided intravascular intervention and cancer diagnosis.
There have been significant advancements in CT technology. Multidetector CT and dual-source CT have been developed and used to reduce the radiation dose and to improve both temporal and spatial resolution. In contrast, little process has been made to address the limitations of CT contrast agents. Current intravascular CT contrast agents are based on biocompatible and highly functionalized water-soluble triiodobenzene derivatives. These small molecular contrast agents do not have favorable pharmacokinetics and are rapidly cleared from the blood circulation. Heusner et al., Eur J Nucl Med Mol I 2007; 34:S294-S. Perfect timing of contrast injection is required to catch the first pass for CT angiography. High doses or multiple doses are often used to generate sufficient contrast enhancement for accurate diagnostic imaging. However, the use of the agents at high doses and multiple doses often induce dose-related toxic side effects. Their rapid clearance at high concentrations from blood circulation may cause acute kidney injury or renal failure. There is an unmet clinical need for safe and effective CT contrast agents that can provide effective CT contrast enhancement at reduced doses and minimize dose related toxic side effects.
The search for safer and effective X-ray contrast agents has been continued for over a century since the first clinical use of X-ray for medical imaging. Besides the small molecular iodinated contrast agents, various polymeric or nanoparticulate contrast agents containing heavy elements have been reported to improve the pharmacokinetics and effectiveness of the iodinated small molecular contrast agents. de Vries et al., Biomaterials, 2010; 31:6537-44. Iodinated contrast agents have been incorporated into biocompatible polymers, polymeric nanoparticles (Trubetskoy et al., J Drug Target 1997; 4:381-8), liposomes (Krause et al., J Liposome Res 2011; 21:229-36) and dendrimers (Peng et al., Biomaterials 2012; 33:1107-19), to prolong the blood circulation of the agents for effective blood pool imaging. Colloids or nanoparticles containing other heavy elements, including thorium, bismuth, gold and etc, have also been reported as effective CT contrast agents. These agents have prolonged vascular circulation and provide sharp blood vessel delineation essential for CT angiography. For example, colloidal thorium oxide (1-1,000 nm in size) was first used for clinical X-ray imaging in 1930s. However, the agent was terminated for intravenous use in 1950s because of its slow excretion from the body and consequent toxic sides, e.g. cancer and liver fibrosis and cirrhosis. Despite the advantages of the polymeric or nanosized contrast agents for CT blood pool imaging, no such an agent has been approved for clinical use since then because of the concerns of potential toxic side effects associated their slow excretion.
Rational design of CT contrast agents with controlled pharmacokinetics and excretion rates is critical to address the drawbacks of both iodinated small molecular CT contrast agents and nanosized contrast agents. The inventors recently designed and developed biodegradable macromolecular MRI contrast agents based on polydisulfides. Lu et al., Int J Nanomedicine. 2006; 1(1):31-40. These agents initially behave as macromolecular agents in the body and produce superior contrast enhancement in the blood pool and soft tissues. The disulfide bonds in the polymer backbone are then gradually reduced by endogenous thiols in plasma via disulfide-thiol exchange reaction to give oligomeric or smaller molecules, which are readily excreted via renal filtration after the imaging. As a result, the polydisulfide based MRI contrast agents produce prolonged blood pool enhancement as macromolecular contrast agents and excrete from the body as small molecular agents with minimal tissue retention. However, there remains a need for novel biodegradable CT contrast agents.